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  3. Screening and discovery of nitro-benzoxadiazole compounds activating epidermal growth factor receptor (EGFR) in cancer cells

Screening and discovery of nitro-benzoxadiazole compounds activating epidermal growth factor receptor (EGFR) in cancer cells

  • Sci Rep. 2014 Feb 5:4:3977. doi: 10.1038/srep03977.
Vehary Sakanyan 1,  Marie Angelini 2,  Mickael Le Béchec 3,  Michèle Françoise Lecocq 2,  Florence Benaiteau 4,  Bénédicte Rousseau 4,  Aram Gyulkhandanyan 5,  Lusine Gyulkhandanyan 5,  Cédric Logé 4,  Eric Reiter 6,  Christos Roussakis 4,  Fabrice Fleury 3
Affiliations

Affiliations

  • 1 1] ProtNeteomix, 29 rue de Provence, 44700 Orvault, France [2] IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
  • 2 ProtNeteomix, 29 rue de Provence, 44700 Orvault, France.
  • 3 FRE-CNRS 3478, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
  • 4 IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
  • 5 Institute of Biochemistry, National Academy of Sciences of Armenia, Yerevan, Republic of Armenia.
  • 6 BIOS group, UMR85 INRA; UMR7247 CNRS; IFCE, 37380 Nouzilly, France.
PMID: 24496106 DOI: 10.1038/srep03977
Abstract

Peptide ligand-induced dimerization of the extracellular region of the epidermal growth factor receptor (sEGFR) is central to the signal transduction of many cellular processes. A small molecule microarray screen has been developed to search for non-peptide compounds able to bind to sEGFR. We describe the discovery of nitro-benzoxadiazole (NBD) compounds that enhance tyrosine phosphorylation of EGFR and thereby trigger downstream signaling pathways and other Receptor Tyrosine Kinases in Cancer cells. The protein phosphorylation profile in cells exposed to NBD compounds is to some extent reminiscent of the profile induced by the cognate ligand. Experimental studies indicate that the small compounds bind to the dimerization domain of sEGFR, and generate stable dimers providing allosteric activation of the receptor. Moreover, receptor phosphorylation is associated with inhibition of PTP-1B Phosphatase. Our data offer a promising paradigm for investigating new aspects of signal transduction mediated by EGFR in Cancer cells exposed to electrophilic NBD compounds.

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